Role of orexin/hypocretin in dependence and addiction

Brain Res. 2010 Feb 16;1314:130-8. doi: 10.1016/j.brainres.2009.08.028. Epub 2009 Aug 20.


The orexins (or hypocretins) are hypothalamic neuropeptides that have been implicated in a variety of behaviors ranging from feeding to sleep and arousal. Evidence from animal models suggests a role for orexins in reward processing and drug addiction. In this review, we discuss orexin's interaction with the mesocorticolimbic reward pathway and the effects of drugs of abuse on the orexin system. We further review models of drug dependence and addiction and describe behavioral alterations that are seen when the orexin system is manipulated both pharmacologically and genetically. Based on the findings reported in the literature thus far, we posit that orexin functioning contributes to both drug reward and drug-related stress/aversive responsiveness; however, diverse anatomical substrates, and perhaps receptor specificity, contribute differentially to reward and stress components.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Hypothalamic Area, Lateral / physiology*
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Neuropeptides / physiology*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiology*
  • Orexins
  • Reward
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / physiopathology
  • Substance-Related Disorders / metabolism
  • Substance-Related Disorders / physiopathology*
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiology*


  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins